Categories: Skeleton phene (incl. short stature & teeth)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 166600 (trait) , 611490 (trait) , 618541 (trait) , 602727 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0012676: autosomal recessive osteopetrosis 4

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2014

History: This disorder was first documented by Sartelet et al. (2014).

Inheritance: Sartelet et al. (2014) reported data consistent with autosomal recessive inheritance.

Mapping: By conducting a GWAS on 33 affected and 275 controls (each genotyped with a custom 50K SNP chip; Charlier et al., 2008, Nat Genet 40, 449-454), Sartelet et al. (2014) mapped this disorder to the proximal end of chromosome BTA25. Subsequent "Visual examination of the SNP genotypes defined a non-recombinant autozygous interval of 1.15 Mb (Bovine Genome assembly bTau6 (UMD3.1), chr25: 632,647-1,781,139) shared by all 33 cases and encompassing 82 annotated transcripts".

Molecular basis: Comparison of whole-genome sequence by Sartelet et al. (2014), from four affecteds and eight control Belgian Blue non-carriers, revealed three SNVs "[c2244G>C + c2248T>C + c2250C>A] located in exon 23 of the CLCN7 gene encoding the anion transport protein ClC-7". The first of these is synonymous, but the second and third jointly cause "a tyrosine to glutamine substitution (TAC>CAA: Y750Q)" in a highly conserved region of the protein. Subsequent genotyping for the two Y750Q missense mutations in "63 cases, 74 of their parents, 141 animals from 11 breeds other than BBCB, and 6,489 healthy BBCB animals" confirmed the causality of these mutations: "All cases were homozygous for the Y750Q mutation, while available parents and putative founder (Gabin) were all carriers. The mutation was absent in the non-BBCB cohort, and detected at a frequency of 5% (644 carriers) in BBCB controls. None of the genotyped controls was homozygous for the mutant (p=0.000026 under Hardy Weinberg equilibrium)."

Clinical features: As reported by Sartelet et al. (2014), "Between 2008 and 2010, we collected biological material with pedigree records for 63 newborn calves with shared symptomatology: affected calves were mostly stillborn (70% of them), slightly premature (gestation length between 210 and 260 days, 73%), displayed a small body size (45%) and abdominal hydrops (58%), an abnormal skull shape (100%), inferior brachygnatism (100%), protruding tongue (81%) and gingival hamartomas of variable size (up to 15 cm diameter, 80%) located on the lower jaw . . . . All calves born alive were blind and consequently euthanized within days or weeks. At necropsy, we observed liver (82% . . . ) and kidney (59% . . . ) hypertrophies. Mothers of affected calves typically suffered from hydramnios, a condition commonly associated with impaired swallowing in the fetus".

Prevalence: Sartelet et al. (2014) reported that 10% of normal Belgian Blues are carriers of the pair of causal mutations.

Breed: Belgian Blue (Cattle) (VBO_0000139).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: